Derivatives of 3, 5-dioxo-pyrazolidine



United-States Patent 2,100,670 DERIVATIVES or 3,5-DIOX0-PYRAZOL1DINEFranz Hiifliger, Basel, Switzerland, assignor to J. R.

Geigy, A. G., Basel, Switzerland, a Swiss firm No Drawing. Originalapplication October 25, 1951,

Serial No. 253,227. Divided and this application August 29, 1952, SerialNo. 307,161

3 Claims. or. 260-310) The present application is a division ofcopending application, Serial No. 253,227, now abandoned, and isconcemed with new derivatives of 3.5-dioxo-pyrazolidine and their saltsand the processes for the production thereof. The new compoundscorrespond to the following general formula:

iikryl or to their tautomeric forms wherein R represents anitrogen-containing radical, and Aryl represents a substituted orunsubstituted phenyl radical.

Halogen atoms, alkyl, hydroxy, alkoxy, acyloxy, nitro, amino,alkylamino, acylamino, carbalkoxy, hydroxyalkyl, carbalkoxyalkyl groupsfor example come into question as substituents of the phenyl radicals.be listed as nitrogen-containing radicals R: NH, N-alkyl, CO-NH, CO-N(alkyl), SOzNH, SO2N(alkyl), HN C0, (alkyl)NCU. These atom groupings canbe in any positioned desired, e. g. in the 04-, {3-, 7-, fi-position.The length of the chain of the radical R including the nitrogen atomshould not consist of more than 10 members. For example, R may representthe following radicals: dimethyl, and 'diethylaminomethyl radicals;methylarnino, ethylamino, propylamino, allylamino, N-methyl-anilino,benzylamino, dimethylamino, diethylamino, piperidino, -ethyl, -propyl,-isopropyl or -butyl radicals; acetamino, N-acetyl-methylamino,N-benzoylmethylamino, N-methane-sulphonyl-ethylamino, N-ethanesulphonyl-methylamino, benzene sulphonyl-amino, -ethyl, -propyl or-butyl radicals; N-ethyl-carbamyl, N-propyl-carbamyl,N.N-dimethylcarbamyl, N .N-diethylcarbamyl, -methyl, -ethyl, -propyl or-butyl radicals and such like.

The defined 1.2-diaryl-3.5-dioxo-pyrazolidines of the Formula I areproduced in principle by condensation of suitable malonic acidderivatives with 1.2-diaryl hydrazines (hydrazo benzenes).

Thus a reactive derivative of a monosubstituted malonic acid of theformula:

wherein X represents a radical of the carboxylic acid derivative whichcan be split oil such as for example halogen (acid halide), an alkoxygroup (ester), etc., can be reacted with a 1.2-diaryl hydrazine of theformula:

Aryl-NHNH-Aryl (III) presence of a condensing agent or advantageously inthe The reaction procedure is given an acid binding agent. in detailbelow.

A prefered method of manufacture consists in heating a dialkyl ester,above all the diethyl ester, of a monosubstituted malonic acid, with adiaryl hydrazine in thepresence of a metal alcoholate, e. g. sodiumethylate or.

The following may replaceable hydrogen atom by a metal atom, such asalkali heating with the condensing agents named, the acyl radical metalsand active alkali compounds.

Other ways of carrying out the same process are described below. Thesemodifications consist in using other reactive derivatives instead of adi-ester of malonic acid fif lgormula H, such as, for example, adihalide, an ester ali e.

Condensation of a diarylhydrazine of Formula III with a malonic acidhalide of Formula II, e. g., the dichloride, takes place in a solventwhich is indifferent to the acid halide, such as ether or benzene. Inorder to repress as far as possible the rearrangement of the diarylhydrazine by the halogen hydracid produced, it is advisable to carry outthe condensation in the presence of an acid binding agent, preferably atertiary organic base such as pyridine or dimethyl aniline. In this casethe reaction takes place even at low temperatures which may suitably bein the neighbourhood of 0 C.

The condensation can be carried out ifunsymmetrical reactive derivativesof malonic acid (Formula II) are used. For example, the ester chlorideClCOCI-I(R)COO-alkyl can be allowing the components to react in theratio of their molecular weights in ether or benzene Instead of a diarylhydrazine of Formula HI and N-acyl derivative of the same, e. g.,N-acetyl-hydrazobenzene, can

the reactive derivative of a malonic also be reacted with especiallywith a dialkyl ester. On

acid of Formula II,

is split off, the ring closing to give the pyrazolidine derivative ofFormula I.

The monosubstituted malonic acids and/ or their reactive derivatives ofFormula II are known to a great extent. They can be produced by theintroduction of the radical R into the malonic ner to that described inaryl To introduce the radical R, the pyrazolidine derivative V or a saltthereof, is reacted preferably in the presence of an acid binding agentwith a compound of the formula RX where X means an elf such as Cl, Br,I, 804R or SOsAryl.

The temperature necessary for the reaction depends on the reactivity ofthe compound-R-X; it is well known, for example, that iodine compoundsreactmore easily than bromine compounds. The setting in of the reactionas well as its course can be easily followed by the formation of the Xions. Generally speaking, temperatures between 0 C. and C. are suitable.

in steps especially treated with a di-' aryl hydrazine III to givefirstly the acyl derivative IV, by-

in the presence of acid or its esters in an analogous man-' thefollowing for the introduction of this radical into the 4-position of a1.2-diaryl-3.5-dioxo-' process for the production;

since it proceeds not from This method consists in introatom or aradical which is split 1 The group R can the diketopyrazolidine V in thepresence of a carbonyl compound of the formula R'=O, Where R' stands fora hydrocarbon radical (alkylidene radical) containing nitrogen atoms,the oxygen atom being bound by two valences from one and the same carbonatom. Because of its simplicity and the good yield this process is ofspecial interest technically.

A variation of thismethod consists in h-ydrogenating the condensationproduct VI derived for example from the dOioxo-pyrazolidine V and thecarbonyl compound R:

' In both cases, hydrogenation is preferably carried out with hydrogenin the presence of a catalyst, such as finely divided nickel, platinumor palladium. Other reducing procedures, such as the use of sodiumamalgam and Wat offer no advantages over this method.

However, it must be noted in connection with this proc- 65s that whenthe radical R contains an aliphatic double bond it is difficu'lt toavoid hydrogenating it and the yield in such circumstances is usuallyunsatisfactory. On the other hand, the corresponding saturatedderivative can be easily prepared.- Consequently the process isprimarily suitable for the manufacture of those pyrazolidine derivativesof Formula I in which the radical -R contains no aliphatic double bonds.

Should the nitrogen atom be in the a-position of the side chain R, incertain cases the corresponding reactive formyl compounds (formic acidester) or glyoxylic acid derivatives, e. g. glyoxylic acid esters can beused in the preceding process as carbonyl compounds.

The dioxo-pyrazolidines of Formula V can be prepared by the methodsknown per se for the manufacture of 1.2-diphenyl-3.S-dioxo-pyrazolidine;the most suitable is the condensation of malonie, ester with thecorresponding diaryl a metal alcoholate, e. g. sodium ethylate.

The substituted pyrazolidine derivatives of; Formula VIare derived fromthe unsubstituted parent compounds V bymethods known per se (Bl. Chem.Soc. Japan, 1931, 6, 1-9; 1932, 7, 45-50).

I Finally a third variation consists of introducing the radical R insteps. This is done by introducing e. g. a nitrogen-containing radicalinto an unsubstituted malonic acid derivative, preferably malonic acidester or 1.2-diaryl- 3.5-dioxo-pyrazolidine of Formula V. Thedioxo-pyrazolidine ring can then be closed by condensation of thesubstituted malonic acid derivative with a 1.2-diaryl hydrazine. Theradical R is then built up in the manner known per se in theintermediate products so obtained of the Formula VII:

dry!

wherein alk or alk' represents a substituted alkyl or alkylidene groupand X represents a replaceable group such ashalogen.

On reacting the intermediate products of- Formula VII, inwhich Xrepresents halogen, with primary or secondary amines, end productsresults in which R contains a substituted amino group. If the aminogroup has still one or two hydrogen atoms, then, it can be acylated withreactive carboxylic orsulphonic acid derivatives.

Any, double linkages. occurring in the side chain R,

also be introduced by hydrogenating hydrazine of Formula III in thepresence of.

- lye.

e. g. in alkylidene compounds can be hydrogenated later to formsaturated end products.

A particular variation of the process for production of end products orcorresponding intermediate products having the nitrogen atom in thea-position of the side chain R, consists in reactingl.2-diaryl-3.5-dioxo-pyrazolidines of the Formula V with formaldehyde toobtain the corresponding methylol compounds. The above 1.2-diaryl-3.S-dioxo-pyrazolidines may also be reacted with formaldehyde andhalogen hydracid to form the corresponding halogen methyl compoundswhich can then be converted into the end products as described above.Also, if the reaction with formaldehyde takes place in the presence ofsecondary aliphatic or cycloaliphatic amines, basic end products areobtained direct.

The 1.2-diaryl-3.5-dioxo-pyrazolidines of Formula I preparable accordingto the invention are useful as therapeutics. They have antiphlogisticproperties.

The compounds can also form salts with basic and acid compounds. .Forexample, water soluble salts are formed with hydrochloric acid.

The salt can be obtained in solid form when desired either byevaporation of the filtered solution or by adding a solvent in which thesalt is insoluble, for example, by the addition of ether to an alcoholicsolution of the salt.

In the following example a method of carrying out the manufacture isdescribed. Parts are by weight. The relationship of parts by weight toparts by volume is that of kilogrammes to litres. The temperatures arein degrees centigrade.

Example 126 parts of, 1.2-diphenyl-3.5-dioxo-pyrazolidine are dissolvedin 525 parts by volume of 2 N caustic soda A solution of 94 parts of,8-chlorethyl-diethylamine hydrochloride in parts of water is then added.and the whole is heated to 85-90 while stirring. After a short time,the 1.2-diphenyl-3.5-dioxo-4(fl-diethylamino ethyl)-pyrazolidine beginsto separate. After heating for 1 hour, the reaction mass is allowed tocool and is then filtered under suction. The residue is dissolved in 2 Ncaustic soda lye, any undissolved particles are filtered off and thefiltrate is made weakly acid to litmus. The precipitate is filtered offunder suction and dissolved in 2 N hydrochloric acid. The solution isfiltered and neutralised with ammonia. The precipitate is drawn offunder suction .and recrystallised from alcohol. It is 1.2 diphenyl 3.5dioxo 4 (B diethylamino ethyl)- pyrazolidine and melts at 228-230 ondecomposition.

The following compounds for example can be prepared by analogous orsimilarmethods to those described above: 1.2 diphenyl 3.5 dioxo 4 ([3dimethylaminoethyl)- pyrazolidine, 1.2 diphenyl 3.5 dioxo 4 ('ydiethylamino propyl) pyrazolidine, 1.2 diphenyl 3.5 dioxo- 4- B-piperidino-ethyl) -pyrazolidine.

What I claim is:

1. A member selected from the group consisting of compounds of theformula:

Lryl

References Cited in the file of this patent St2enzl et al.: ChemicalAbstracts, vol. 46, col. 105,

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA: